Malaria caused by Plasmodium falciparum remains a major public health threat. Over 225 million cases of malaria occur annually among the worlds poorest populations, claiming the lives of nearly a million children each year in Africa alone. The widespread implementation of malaria control interventions such as artemisinin-based combination therapy and insecticide-treated bed nets is hampered by the poor health-care infrastructure of many malaria-endemic countries. Moreover, P. falciparum has proven adept at acquiring and rapidly spreading resistance to antimalarial drugs, and vector control is constantly threatened by the inevitability of the emergence of insecticide-resistant mosquitoes. Ultimately, a key tool for the control, elimination, or even eradication of malaria is an effective vaccine, yet vaccine candidates in clinical development confer only partial protection at best. The development of a highly effective malaria vaccine has been hindered in part by a poor understanding of the interaction between P. falciparum and the human immune system. Importantly, protective immunity to malaria can be acquired after repeated P. falciparum infections but wanes rapidly in the absence of ongoing exposure. The quality of the innate and adaptive immune responses that ultimately confers this protection and the mechanisms that underlie their inefficient acquisition and rapid loss are largely unknown. Our objective is to aid malaria vaccine development by addressing these critical knowledge gaps. To this end, we apply recent advances in immunology and genomics-based technology to rigorously conducted longitudinal cohort studies in malaria-endemic areas to deepen our understanding of the interaction between P. falciparum and the human immune system and to define molecular and cellular signatures of malaria immunity. We have five main objectives: 1) obtain high quality clinical data and biospecimens from longitudinal cohort studies in Mali in which exposure to P. falciparum infection and protection against malaria are reliably assessed, 2) determine the antigen specificity, function, kinetics and cellular basis of the antibody response to P. falciparum, 3) define the mechanisms by which P. falciparum-induced inflammation is regulated, 4) identify a molecular signature of immunity to malaria through systems biology approaches, and 5) determine the relationship between persistent asymptomatic P. falciparum infection and malaria risk, and elucidate the host and parasite factors that underlie this phenomenon. The large cohort studies we conduct in Mali are made possible through a close collaboration with an experienced team of clinicians and scientists at the Malaria Research and Training Center (MRTC) at the University of Bamako. To expand the scope of our work and to maximize the knowledge gained from our cohort studies in Mali, we collaborate with experts in parasite biology, basic immunology, genomics and computational biology. For example, in 2012 we initiated a new collaboration with the J. Craig Venter Institute to incorporate powerful sequencing-based technologies into the analysis of our cohort studies in Mali. Genomic and transcriptomic signatures that correlate with protection from malaria may yield new hypotheses regarding the biological mechanisms through which malaria immunity is induced by natural P. falciparum infection. If successful, this and other ongoing projects have the potential to contribute not only to a better understanding of the acquisition and maintenance of immunity to malaria, but also to provide insights into the mechanisms at play in human immune responses to infectious diseases more generally.